Progress to Date
After years of research demonstrating the extent of this problem,
coupled with advocacy by national professional societies in paediatrics
and child health, there was movement in this area when the Pediatric
Pharmacology Research Unit (PPRU) network was established in the United
States by the Eunice Kennedy Shriver National Institute of Child Health
and Human Development in 1994. This network – a group of first seven
and then thirteen academic health care centre which operated from 1994
to 2010 – had the mandate to improve the paediatric labelling of both
new drugs and drugs already on the market by conducting collaborative
research with academia, industry and health care providers (42). Over
the life span of the PPRU, a number of advances were made in
understanding the impact of ontogeny on therapy for children and in the
design and conduct of drug studies in infants and children.
The development of the PPRU network was accompanied by legislative
change, the first being the Pediatric Labelling Rule of 1994, issued by
the US FDA. This rule, which requested industry to submit paediatric
data, was fairly ineffective in enhancing paediatric labelling and thus
in 1997 the FDA Modernization Act (FDAMA) was passed (43). FDAMA
provided incentives for companies to include paediatric data in new drug
submissions by extending 6 months of patent protection for drugs when
submission includes paediatric data. Failing to achieve the desired
effect, in 1998, the first iteration of a “Pediatric Rule” was enacted
which mandated paediatric studies for not only new drugs but also for
any label changes on already approved and marketed drugs. This rule,
however, was challenged in Federal court and was ultimately struck down
in 2002, citing Agency overreach.
Despite this early setback, the United State Congress persisted, and the
Best Pharmaceuticals for Children Act (BPCA) passed in 2002 while the
Pediatric Research Equity Act (PREA) passed a year later in 2003.
Together, these two pieces of legislation imposed a regulatory
requirement for pharmaceutical companies to evaluate drugs in paediatric
populations if they were likely to be used in children, irrespective of
the indication for which approval was sought (43).
The provision of paediatric exclusivity was successful in having
paediatric-specific data on the project monograph when an FDA request
for paediatric data was issued in 92% of all requests for which
exclusivity was granted from 1998 to 2012 (44). This provision allows
six additional months of patent exclusivity to manufacturers who conduct
paediatric drug studies and have a Pediatric Study Plan (PSP). However,
of 401 requests made by the FDA exclusivity was only granted in 189
cases, i.e. the majority of requests did not result in new paediatric
data or indications (44). This was influenced by both therapeutic area
and year of exclusivity, with requests made in the areas of
gastroenterology and pain and requests made in the early years of the
program being more likely to result in additional paediatric data or
indications (44).
Similar regulatory progress has been made internationally. In Europe,
the European Medicines Agency (EMA), after studying developments in the
United States, enacted the Paediatric Regulation in 2007 with the goal
of enhancing the development, availability and safety of medications for
children in the European Union (45). An important aspect of the
Regulation was the requirement for a Paediatric Investigation Plan (PIP)
for all new drug submissions except when a waiver or deferral is
granted, as in the case of a drug that will not in any reasonable
likelihood used for children. The Regulation also established a
Paediatric Committee to determine which studies must be carried out as
part of the PIP. The FDA requires a Pediatric Study Plan and also has a
Pediatric Expert Committee.
A ten year analysis of the implementation of the Paediatric Regulation
demonstrated that there had been a substantial increase in the number of
medications with paediatric data and/or indications, notably in the
areas of rheumatology and anti-infective agents. However, in diseases
largely confined to children alone or where there were substantial
differences in disease course between adults and children there was much
less progress. As a consequence, the EMA and the Paediatric Committee
created an action plan to enhance implementation of the Regulation. The
action plan includes identifying paediatric medical needs, strengthening
cooperation between decision makers, ensuring the timely completion of
PIPs, improving how PIPs are handled and increasing transparency around
paediatric medicines.
While both the US FDA and the European Union’s EMA had common goals to
enhance the development of more safe and effective therapeutics for
children they have pursued slightly different approaches (Table 1) (45).
As an example, the FDA had two separate sets of legislation – BCPA and
PREA – to drive drug development for children with a third - Research
to Accelerate Cures and Equity for Children Act (the RACE Act) being
introduced in 2017 while the EU has a single piece of legislation,
reducing the number of requirements and legal frameworks to be
negotiated. This does not, however, necessarily mean that it is easier
to navigate the EMA’s paediatric requirements as opposed to the FDA.
While there are other differences overall this legislative approach in
both the US and the European Union not only is the goal the same but so
are the scientific elements driving paediatric investigation, including
but not restricted to descriptions of products and diseases, development
plans for age-appropriate formulations and timing of studies (45).
The developments in the US and European Union to move paediatric drug
development forward have stimulated changes in the approach to
paediatric drug approval and regulation in a number of countries
although the US and the European Union remain the only two large
jurisdictions to have comprehensive paediatric drug development
strategies supported by legislation although some smaller jurisdictions
such as Switzerland that require paediatric data, often via the approval
of an approved PIP or PSP (26, 46-48).